The principles objective of this research is the development of new methods and synthetic strategies with which to address the preparation of macrocyclic ansa compounds exhibiting antitumor and antiviral properties. Specific targets include in the benzoquinoid ansamycins herbimycin A, B and C, geldanamycin and the naphthoquinoid ansamycins streptovaricins C and D. The antiproliferative activity of the benzoquinoid ansamycins stems from their ability to inhibit the action of oncogene-derived protein tyrosine kinases (PTKs), and observation with significant implications both for clinical efforts to develop effective antitumor and antiviral strategies and for fundamental investigations of the intracellular events surrounding cell growth and differentiation. Tyrosine kinases have recently been identified as the oncogene products of transforming retroviruses and appear at elevated levels in a number of different malignant cells types, including leukemias, lymphomas and carcinomas. The implication of PTKs as causative factors in pathological states resulting from uncontrolled cells proliferation present a strategic molecular opportunity for antitumor and antiviral chemotherapy. The ability of herbimycin A to synchronize the growth cycles of treated cell populations suggests a combination chemotherapeutic strategy involving administration in conjunction with cytotoxic agents which act on cells actively engaged in DNA synthesis. A long range goal of the proposed synthetic program is the development of a comprehensive, preparatively useful scheme for the synthesis of polyketide-derived acyclic arrays based on the serial application of diastereoselective sigmatropic rearrangements. This general strategy presents unique opportunities to address the synthesis of polypropionate- polyacetate based targets of biological significance, including the immunomodulator rapamycin, the ionophore antibiotic zincophorin, the macrolide antibiotic tylosin and (2S,3S,,8S,9S)-Adda, a novel beta- aminoacid component of the biologically active peptides nodularis and motuparin. A secondary component of this long-range program involves the investigation of new synthetic methodology which addresses specific structural and stereochemical features of the ansamycins and related natural products. In conjunction with the propose ansamycin studies, the [2,3]. Witting rearrangement of new substrate classes which establish the structural elements of polyacetate and polypropionate-derived acyclic systems will be examined